64 replies to this topic

[nickthird]

White lotus has a mild transient effect for about 30 min-1hr at around 30mg of x100 powder extract. At 15mg there is almost no effect.

[StevesPetMacaque]

This article provides an interesting perspective on the role of chronic dopaminergic overstimulation and KOR activity:

During cocaine binges, not only do dopamine levels rise in the brain, activating dopamine receptors, but there is a concomitant increase in μ and κ-receptor activity as well. Increased κ-receptor activation, via dynorphin, seems to lower dopamine levels. The increase in pre-dynorphin mRNA in response to cocaine binges in rats is blocked by dopamine receptor antagonists. Further data from animal studies indicate a directly proportional relationship between dopamine levels in the nucleus accumbens, substantia nigra, and striatum, and tonic dynorphin levels in these areas. As dopamine receptors are activated in these regions, dynorphin levels increase. Sivam et al. concluded that chronic dopaminergic stimulation (via cocaine in this study) was required to increase dynorphin levels in areas of the brain, and that acute sporadic use would not increase dynorphin levels or κ-agonism. When dopamine receptors are blocked by an antagonist, the increased activation of κ-receptors/expression of dynorphin is also blocked,4 an observation found more consistently with blockade of the dopamine-1 receptor subtype in relation to the dopamine-2 receptor subtype. This reciprocal increase is noted in the ventral tegmental area as well, where acute increases in κ-receptor activity decrease dopamine levels in the prefrontal cortex. However, κ-receptor activity does not seem to maintain dopamine tonicity in the prefrontal cortex. Chronically activated κ-receptors associated with decreased dopamine concentrations, reversible upon κ-antagonism, have also been noted in the hypothalamus.

 

As dynorphin levels increase (ie, κ-receptors are activated), synaptic dopamine levels decline. Studies show that dynorphin blocks both the release, and increases the re-uptake, of dopamine in the synapse. It is apparent that through its substrate peptide dynorphin, κ-receptors function as part of a negative feedback loop to buffer increases in dopamine levels, favoring maintaining a steady tonic level. Increased dopamine levels in the nucleus accumbens, striatum, and the ventral tegmental area are inherent to the reward and salience that drive substance dependence. Data from animal studies suggest that ingestion of alcohol upregulates dopamine activity. Alcohol administration has been found to increase PDYN mRNA expression in ventral and dorsal striatum and the nucleus accumbens, leading to an increased dynorphin concentration in these areas. This increase in dynorphin/kappa activity can last up to 21 days with abstinence.

[Rorororo]

 

This article provides an interesting perspective on the role of chronic dopaminergic overstimulation and KOR activity:

 

 

 

So, is this saying from:

 

 

 

dynorphin levels or κ-agonism

 

 

That KOR agonists do NOT cause down regulation over time?

 

Therefore, an antagonist should permanently cause down-regulation?

 

There is alot of contradicting info out there on this topic and little info (from this I do jumps which isn't always accurate)...

 

I would stack a KOR antagonist with GDNF to play it safe though. 

[StevesPetMacaque]

No, it doesn't address the effects of KOR agonists on the KOR receptors. Rather, it finds that chronic dopamine agonism increases dynorphin and KOR activity, though acute activity does not. This means that one must change behaviors away from dopaminergic overstimulation, or permanently take KOR antagonists. It also notes that after the removal of the chronic overstimulation (in this case, from alcohol), KOR activity was enhanced for 3 weeks in rats, so who knows how much longer that might be in humans? Months? Years?

 

In either case, one should avoid continual overstimulation, or face increased KOR activity and hence a sense of dissociation/depersonalization.

 

Furthermore, chronic KOR antagonism is probably ill-advised. As we all (hopefully, by now) know, impaired synaptic plasticity is a hallmark of depression and other neuropsychiatric disorders, mTOR activation is required for synaptic plasticity, and antidepressant efficacy is associated with mTOR activation. I have found evidence that KOR agonism activates mTOR, experiments that test the connection between KOR, mTOR, and depression, and results that opioid antagonists can block mTOR.

 

All of this suggests that it would be wise to use KOR antagonists sparingly, and cut the problem off at the source to the extent possible.

[Rorororo]

No, it doesn't address the effects of KOR agonists on the KOR receptors. Rather, it finds that chronic dopamine agonism increases dynorphin and KOR activity, though acute activity does not. This means that one must change behaviors away from dopaminergic overstimulation, or permanently take KOR antagonists. It also notes that after the removal of the chronic overstimulation (in this case, from alcohol), KOR activity was enhanced for 3 weeks in rats, so who knows how much longer that might be in humans? Months? Years?

 

In either case, one should avoid continual overstimulation, or face increased KOR activity and hence a sense of dissociation/depersonalization.

 

Furthermore, chronic KOR antagonism is probably ill-advised. As we all (hopefully, by now) know, impaired synaptic plasticity is a hallmark of depression and other neuropsychiatric disorders, mTOR activation is required for synaptic plasticity, and antidepressant efficacy is associated with mTOR activation. I have found evidence that KOR agonism activates mTOR, experiments that test the connection between KOR, mTOR, and depression, and results that opioid antagonists can block mTOR.

 

All of this suggests that it would be wise to use KOR antagonists sparingly, and cut the problem off at the source to the extent possible.

 

That wasn't exactly what I was asking\addressing. 

 

I am not saying this to you but its my biggest pet peeve when I ask\state something and someone answers back with a politician answer (pretend they didn't hear the question correctly and start answering random stuff)

 

There is doubt on the issue whether KOR up regulation will happen after a period of KOR antagonism. I am curious about this and I am sure others are too...